Cortical Stimulation Paired With Volitional Unimanual Movement Affects Interhemispheric Communication

Abstract

Cortical stimulation (CS) of the motor cortex can cause excitability changes in both hemispheres, showing potential to be a technique for clinical rehabilitation of motor function. However, previous studies that have investigated the effects of delivering CS during movement typically focus on a single hemisphere. On the other hand, studies exploring interhemispheric interactions typically deliver CS at rest. We sought to bridge these two approaches by documenting the consequences of delivering CS to a single motor cortex during different phases of contralateral and ipsilateral limb movement, and simultaneously assessing changes in interactions within and between the hemispheres via local field potential (LFP) recordings. Three macaques were trained in a unimanual reaction time (RT) task and implanted with epidural or intracortical electrodes over bilateral motor cortices. During a given session CS was delivered to one hemisphere with respect to movements of either the contralateral or ipsilateral limb. Stimulation delivered before contralateral limb movement onset shortened the contralateral limb RT. In contrast, stimulation delivered after the end of contralateral movement increased contralateral RT but decreased ipsilateral RT. Stimulation delivered before ipsilateral limb movement decreased ipsilateral RT. All other stimulus conditions as well as random stimulation and periodic stimulation did not have consistently significant effects on either limb. Simultaneous LFP recordings from one animal revealed correlations between changes in interhemispheric alpha band coherence and changes in RT, suggesting that alpha activity may be indicative of interhemispheric communication. These results show that changes caused by CS to the functional coupling within and between precentral cortices is contingent on the timing of CS relative to movement.

Keywords: alpha coherence; electrical cortical stimulation; interhemispheric inhibition; motor cortex; non-human primate; timing-dependent plasticity.

FIGURE 1

Cortical circuitry during unilateral movement. When the animal is at rest, baseline interhemispheric inhibition (IHI) between the motor cortices is depolarized. Unilateral movement activates the contralateral cortex, triggering IHI to the ipsilateral cortex and disinhibiting itself.

FIGURE 2

Behavioral task, experimental timeline, and stimulus timing. (A) Top: Monkeys were cued to move a cursor into a target box by rapid wrist extension. Trials were randomly selected to be left or right. Bottom: example right hand trial. (B) Experimental timeline showing trials before (Pre), during (Cond) and after (Post) cortical stimulation (CS). The task was performed continuously throughout the experiment. (C) Stimulus timings are shown with respect to the average accelerometer trace across trials. The stimulus timing was split into three groups relative to movement onset (RT at 0): CS_prep, CS_move, and CS_relax.

FIGURE 3

Estimating reaction time. (A) Three example trials. Boxes indicate when the monkey was cued to move left (red box) or right (blue box). Responses were required to be unilateral. Inset: identification of reaction time (RT). Raw accelerometer signal (gray) is transformed into a processed signal (black) for RT estimation using a threshold (dotted line). Note the stimulus induced twitch lies below the threshold. (B) Aligned processed accelerometer traces. Left: aligned by GO signal. Right: aligned by calculated RT.

FIGURE 4

Contralateral CS. (A) Example illustration of Contralateral CS and task relationship for left hemispheric stimulation. (B) Difference between RTs for trials during the Cond epoch and the median RT of the Pre epoch for each monkey (ΔRT). CS_prep significantly decreased tRT in all monkeys. CS_relax experiments produced bilateral effects, significantly slowing down tRT and speeding up ntRT. Significance is calculated in comparison with the no stimulation control experiments and only denoted if consistent across all animals (*p < 0.01; **p < 0.001; ***p < 0.0001).

FIGURE 5

Ipsilateral CS. (A) Example illustration of Ipsilateral CS and task relationship for left hemispheric stimulation. (B) Difference between RTs for trials during the Cond epoch and the median RT of the Pre epoch for each monkey. CS_prep decreased tRT in both monkeys. Significance is calculated in comparison with the no stimulation control experiments and only denoted if consistent across both animals (**p < 0.001).

FIGURE 6

Persistence of changes in RT. (A) RT changes of trials ipsilateral to the stimulated hemisphere stayed faster during Post epoch of CS_relax experiments in Monkeys I and K. Increases in CRT did not persist (*p < 0.01; **p < 0.001; ***p < 0.001). (B) Effects of CS were persistent in trials arriving long after CS was delivered during experiments with consistently timed CS. (*p < 0.01; **p < 0.001; ***p < 0.001).

FIGURE 7

Control Experiments. (A) RT relative to the Pre epoch when delivering no stimulation during the “Cond” epoch. The “Cond” epoch was determined using the number of trials. RT slows over time for both limbs and becomes significant by the Post epoch. There was no significant difference between the two limbs. Significance is compared to zero (*p < 0.01). (B) Periodic stimulation delivered to one hemisphere did not have consistent changes or produce differential effects in RT associated with either hand. Plots show six different experiments with Monkey I and corresponding change in RT. Contra and Ipsi RT are with respect to the stimulated hemisphere. Significance is compared to zero (*p < 0.01; **p < 0.001). (C) Random stimulus timing delivered to both the movement generating (Contra CS) and non-movement generating (Ipsi CS) hemisphere. There is greater variability in RT compared to the no stimulation condition, but median changes were similar. Significance is compared to zero (*p < 0.01).

FIGURE 8

Spectral power and coherence during a trial. (A) Spectral power during behavior with respect to the GO signal of the contralateral (top) and ipsilateral hemispheres (bottom) during a Pre epoch, averaged across all three monkeys. The right panels show the spectra normalized across time for each frequency (z-score) to highlight frequency-specific changes over time. (B) Coherence between the two hemispheres with respect to the GO signal. The right panel shows coherence normalized across time for each frequency.

FIGURE 9

Neural dynamics of movement. RT-averaged raw LFP, instantaneous alpha (α), beta (β), and low gamma (γ) intrahemispheric amplitudes, interhemispheric α and β coherence (Coh), and processed accelerometer signal (Accel). Solid lines depict the contralateral hemisphere’s trial-triggered averages, and dashed lines depict the ipsilateral hemisphere’s trial-triggered averages.

FIGURE 10

Change in amplitude and coherence over time with no stimulation. (A) RT-aligned alpha (α, top) and beta (β, bottom) intrahemispheric amplitude and interhemispheric coherence for all three epochs of no stimulation control experiments. Contralateral and ipsilateral refers to the hemisphere relative to movement. (B) Accelerometer traces showing larger movements during the Pre epoch compared to the Cond or Post epochs during no stimulation control experiments.

FIGURE 11

Coherence in Contralateral CS experiments. Coherence during each experimental epoch for CS_prep and CS_relax. Contralateral and ipsilateral refers to limb movement relative to the stimulated hemisphere. Notice the large decrease in contralateral alpha coherence during CS_prep and ipsilateral alpha during CS_relax (arrows); both RTs decreased during stimulation (Figure 3). CS_move did not produce any significant changes. See Supplementary Figure 5 for both alpha and beta coherence for all Contralateral CS conditions.

FIGURE 12

Alpha coherence reflects changes in RT. Normalized changes in the integrated interhemispheric alpha coherence peak from the Pre epoch to the Cond epoch (difference between the coherence in the Pre and Cond epochs divided by the coherence in the Pre epoch). The changes in alpha coherence reflect the changes in Monkey U’s RT induced by each CS timing for (A) Contralateral CS and (B) Ipsilateral CS. Statistical testing compares the changes to the control experiment. (*p < 0.01, **p < 0.001, ***p < 0.0001).

FIGURE 13

Cortical circuitry affected by stimulation. Intra- and interhemispheric circuitry involved in unilateral movement. Numbers identify proposed affected connections with left hemispheric stimulation for (1) decrease in tRT during Contralateral CS_prep, (2) decrease in tRT during Ipsilateral CS_prep, (3) increase in tRT after Contralateral CS_relax, and (4) decrease in ntRT after Contralateral CS_relax.